Depression, Schizophrenia, Bipolar Disorder (green slides)

What is the MOA of Tricyclic antidepressants (TCAs)

• Non-selective inhibition of NE and serotonin (5-HT) reuptake allowing for increased NE to bind to receptors at the synaptic cleft

• Secondary amines more selective for NE

• While it was the earliest available it is now reserved for refractory disease

What are the Tricyclic Antidepressants (TCA) TERTIARY AMINES

• Amitripyline (Elavil)

• Doxepin (Sinequan)

What are the Tricyclic Antidepressants (TCA) SECONDARY AMINES

Nortriptyline (Pamelor)

What are the adverse effects of TCAs?

Have activity against the receptors listed below (secondary amines less so than tertiary amines):

• Histamine receptors (H1 receptors)

  • leading to sedation, weakness, fatigue

• Cholinergic receptors (anti-SLUDGE effects)

  • leading to dry mouth, blurred vision, constipation, urinary retention

• Alpha-1 receptor blockade

  • leading to hypotension

• Sodium channel blockade

  • leading to arrhythmias, QTc prolongation

• Other: sexual dysfunction, seizure potential, weight gain, photosensitivity, withdrawal if stopped abruptly (titrate slowly)

What are the drug interactions with TCAs?

• Monoamine oxidase inhibitors (MAOI)

  • MAO-Is inhibits the breakdown of neurotransmitters (ie dopamine, serotonin, NE)

  • leads to hypertension, tachycardia, serotonin syndrome

• SSRIs

  • may lead to serotonin syndrome

• Alcohol and other CNS depressants

  • may cause additive effects such as (drowsiness, dizziness), worsen depression

What are the adverse effects of MAOIs?

• Postural hypotension

• Hypertensive crisis (food interaction)

• Sleep disturbances, weight gain

• MAO inhibition may persist for up to 10-14 days following discontinuation

Which drugs have a significant interaction with MAOIs?

TCAs

SSRIs

What are the drug-food interactions related to MAOIs?

• Tyramine content (aged cheeses, meats, yeast extract, red wine, bananas)

  • pts should be careful of how much of these foods they consume

• Tyramine increase in NE and tyramine leading to increased HTN causing hypertensive crisis + excitatory effects

What are selective-serotonin reuptake inhibitors (SSRIs)?

First line tx for depression

What are the selective-serotonin reuptake inhibitors (SSRIs)?

• Fluoxetine (Prozac, Prozac weekly)

• Paroxetine (Paxil, Paxil CR)

• Sertraline (Zoloft)

• Fluvoxamine (Luvox)

• Citalopram (Celexa)

• Escitalopram (Lexapro)

What is the MOA for Selective-Serotonin Reuptake Inhibitors (SSRIs)?

• Blocks serotonin transporter (SERT) = block reuptake of 5HT into presynaptic neuron → increased circulating 5HT for post-synaptic uptake

• Targeted the results of TCAs without the histamine/cholinergic/adrenoceptor properties

What is the half life of Fluoxetine and is it an active metabolite?

half life ~5 days (requires 5-week washout)***

YES active metabolite

What is the half-life of SSRIs that are not fluoxetine?

24 hrs (takes about 5 days to wash out of body)

What are the adverse effects of Selective-Serotonin Reuptake Inhibitors (SSRIs)?

• CNS:

  • Fluoxetine = activating (insomnia) - take in AM

  • Paroxetine = sedating - take in PM

• GI:

  • Nausea, vomiting, diarrhea

• Hematologic (monitor):

  • Increased risk of bleeding, especially with aspirin, NSAIDs, anticoagulants

    • Normally 5HT taken up by platelets which augments platelet aggregation so when this blocked it can cause bleeding

• Sexual dysfunction:

  • Highest incidence, cause for pts to switch

• Weight gain:

  • Paroxetine > all others

• Cardiovascular:

  • QT prolongation with citalopram and escitalopram

• Withdrawal syndrome:

  • GI complaints, flu-like symptoms, anxiety, insomnia

• Incidence of orthostatic hypotension, sedation, anticholinergic side effects, and cardiovascular effects are significantly less than TCAs

What are the drug interactions of Selective-Serotonin Reuptake Inhibitors (SSRIs)?

• Significant interactions of MAOIs, TCAs, SNRIs, 5HT OTC supplements (serotonin)

• Wait up to 5 weeks (e.g. fluoxetine) after stopping SSRI before starting a MAOI

• Wait 2 weeks after stopping a MAOI before starting SSRI

What are the Tetracyclic and Unicyclic drugs?

Bupropion (Wellbutrin)

What is the mechanism of action for Bupropion (Wellbutrin)?

Block reuptake of dopamine and NE

What form is Bupropion (Wellbutrin) available in?

Oral formulation

What is the Pharmacokinetics of Bupropion (Wellbutrin)

Hepatically metabolized through CYP 2D6

What is Bupropion (Wellbutrin) used for?

Adjunctive therapy for depression and management of smoking cessation

What are the adverse effects of Bupropion (Wellbutrin)?

• Lowers seizure threshold, which can occur at high doses and abrupt withdrawal

• Activating (tremor, insomnia)

• No sexual dysfunction or weight gain

What is the MOA for Selective-Norepinepherine Reuptake Inhibitors (SNRIs)

Bind to serotonin (SERT) and NE transporters which prevent reuptake of both 5HT and NE (selective for NE) → more excitatory response bc of increase norepi

What are the Selective-Norepinepherine Reuptake Inhibitors (SNRIs)?

• Venlafaxine (Effexor)

• Dexvenlafaxine (Pristiq)

• Duloxetine (Cymbalta)

• Milnacipran (Savella)

What form is Selective-Norepinephrine Reuptake Inhibitors (SNRIs) available in?

Oral

What are the adverse effects of SNRIs?

• Hypertension (NE)

• Sexual dysfunction

• Insomnia (take in the morning)

• Nausea

What is the general management of depression?

Antidepressant pharmacotherapy initiated, follow-up in 2 weeks

Assess response in 4-6 weeks

What is the management of depression with partial or no response within a 2-week time frame?

Assess adherence; increase dose if clinically indicated and no issues with tolerability; for severe symptoms consider ECT

What is the management of depression with partial or no response within a 2-week time frame?

Maintain tx if no issues with tolerability

What is the management of depression with partial or no response in a 4-6 week time frame?

• Increase dose OR change in alternative antidepressant in same class

• OR change/augment with psychotherapy OR

• initiate pharmacotherapy augmentation OR consider ECT

What is the management of depression with full response in a 4-6 week time frame?

Move to continuation phase

What do you do if a pregnant patient has mild to moderate depression?

• Discontinue pharmacotherapy unless severe hx

• CBT or interpersonal psychotherapy

What do you do if a pregnant patient has severe depression?

• Initiate/continue pharmacotherapy

• Prescribe Sertraline because it is least likely to cross into breast milk

• Prescribe paroxetine/fluoxetine which has birth defects so it is only ok to continue if previously failed multiple therapies

What is the MOA of Brexanolone (Zulresso)?

Allosteric modulator of GABA-a; and is chemically identical to allopregnanolone

What is Brzanolone (Zulresso) used to treat?

Post-partum depression

What is the pharmacokinetics of Brexanlone (Zulresso)?

• Restores dysregulated neural network activity associated with depression

  • Upon delivery, allopregnanolone drops drastically after labor --> may contribute to depression

  • This drug works as a supplement to replace allopregnanolone after labor

• One-time 60-hour infusion

• Indicated for those with no response to SSRIs at 6-8 weeks

Do you need to stop breast feeding with Brexnolone?

Do not need to stop breastfeeding

What is Brexanolone (Zulresso) infusion side effect?

• Sedation/loss of consciousness (dose related)

  • Start in AM to best assess degree of sedation

• Requires pulseox during infusion and medical supervision during 60-hour infusion

What are schizophrenia POSITIVE symptoms?

• Delusions

• Hallucinations

• Disorganized speech

• Unusual behavior

• Hostility

• Excitement

• Grandiosity

What are schizophrenia NEGATIVE symptoms?

• Blunted affect

• Lack of motivation and pleasure

• Emotional withdrawal

• Uncooperativeness

• Social withdrawal

• Poverty of speech

What are schizophrenia symptoms?

acute episodes of psychosis ("positive symptoms") often accompanied by a decline in overall functioning over time secondary to "negative symptoms"

WHat is the MOA of Antipsychotic class of drugs?

• Dopamine (D2) receptor blockers inhibit the release of DA and thereby alleviate the POSITIVE symptoms of schizophrenia

• Serotonin (5-HT) agonist/antagonist can alleviate the NEGATIVE symptoms of schizophrenia

What is the relief timeline for Antipsychotics?

• Initially: improvements in aggression

• 2-8 weeks: attention, anxiety, socialization (negative sx)

• Late > 8 weeks: hallucinations, disturbances (positive sx)

What is the MOA for Typical Antipsychotics?

• MOA: D2 receptors antagonists (also block muscarinic, histamine, and alpha-1 receptors)

• Which only has an effect on positive symptoms

What are the Typical Antipsychotics drugs?

• Phenothiazines:

  • Chlorpromazine (Thorazine)

  • Fluphenazine (Prolixin)

• Butyrophenones:

  • Haloperidol (Haldol)

What are the available forms for

Chlorpromazine (Thorazine) , Fluphenazine (Prolixin), and Haloperidol (Haldol)

• Phenothiazines:

  • Chlorpromazine (Thorazine) = tablet, injection

  • Fluphenazine (Prolixin) = tablet, injection, solution, depot

• Butyrophenones:

  • haloperidol (Haldol) = tablet, injection, solution, depot for ACUTE psychosis

  • Haldol avoid IV at all costs (especially bc orthostatic hypotension), go for IM

What are the adverse effects of Typical Antipsychotics

• Anticholinergic side effects

• Orthostatic hypotension

• QTc prolongation

• Extrapyramidal side effects

• Hyperprolactinemia

What are the Atypical Antipsychotics drugs?

• Clozapine (Clozaril)

• Olanzapine (Zyprexa)

• Quetiapine (Seroquel)

• Aripiprazole (Abilify) / Aristada IM

What is the MOA of Atypical Antipsychotics?

Block D2 receptors (lesser extent vs typicals) AND 5HT-2A receptors

What are the advantages of Atypical Antipsychotics?

less sedation, movement disorders, and tardive dyskinesia

What are the disadvantages of Atypical Antipsychotics?

more weight gain and metabolic disturbances (e.g. diabetes)

What is the MOA of Aripiprazole (Abilify)?

Partial D2 agonist, 5HT agonist, 5HT antagonist

What form is Apriprazole (Abilify) available in?

Oral and IM

What are the advantages of Apriprazole (Abilify)?

• Less extrapyramidal symptoms and weight gain

• It may be better tolerated then other

How often is Apriprazole (Abilify) given IM?

• IM available every 4 or 6 weeks

• Aristada® - newest formulation given every 6 weeks•

• Must continue po treatment during thefirst 3 weeks when transitioning

What other condition can Apriprazole (Abilify) treat?

Bipolar disorder

What are the adverse effects of Aripiprazole (Abilify)?

• cardiovascular: prolongation of QT

  • less common with aripiprazole

• neurologic effects: sedation

• anticholinergic effects: dry mouth, urinary retention, constipation

• weight gain (greatest with clozapine and olanzapine)

• impaired glucose tolerance

  • clear risk of DM in pts treated with atypical antipsychotics

  • monitor A1c periodically

• sexual dysfunction

• hematologic: clozapine may cause agranulocytosis so you NEED TO MONITOR CBC

What are the newer Second Generation Antipsychotics and what doe they treat?

• Brexpiprazole (Rexulti)

  • schizophrenia, MDD, agitation associated with dementia due to Alzheimer's disease

• Cariprazine (Vraylar)

  • schizophrenia and BD

• Both have complex (theoretically better targeted) mechanisms of action (sub-receptors)

What are the adverse side effects for the newer Second Second generation Antipyschotics?

• Similar side effect profile to Aripiprazole:

  • cardiovascular: prolongation of QT

    • less common with aripiprazole

  • neurologic effects: sedation

  • anticholinergic effects: dry mouth, urinary retention, constipation

  • weight gain (greatest with clozapine and olanzapine)

  • impaired glucose tolerance

    • clear risk of DM in pts treated with atypical antipsychotics

    • monitor A1c periodically

  • sexual dysfunction

  • hematologic: clozapine may cause agranulocytosis so you NEED TO MONITOR CBC

• Brexpiprazole has slightly more weight gain seen in MDD studies but less EPS symptoms

What is Xanolemine/tropsium chloride (Cobenfy) used for?

new approach to tx schizophrenia approved in Sept. 2024 after 5 week study

Xanolemine/tropsium chloride (Cobenfy) MOA

muscarinic agonist (M1, M4)/ antagonist (peripheral)

Xanolemine/tropsium chloride (Cobenfy) adverse events and contraindications

• adverse events: anticholinergic effects (opposite of SLUDGE)

• contraindications: pts with urinary retention, moderate to severe hepatic impairment